Improving the preclinical and clinical success rates of LMW drugs depends on radical revisions to the status quo scientific foundations of medicinal chemistry: a case study on COVID Mpro inhibition (preprint)

ABSTRACT

The poor preclinical and clinical success rates of low molecular weight compounds is partially attributable to the inherent trial-and-error nature of pharmaceutical research, which is limited largely to retrospective data-driven, rather than prospective prediction-driven workflows stemming from 1) inadequate scientific understanding of structure-activity, structure-property, and structure-free energy relationships; 2) disconnects between empirical models derived from in vitro equilibrium data (e.g., Hill and Michaelis-Menten models) vis-a-vis the native non-equilibrium cellular setting (where the pertinent metrics consist of rates, rather than equilibrium state distributions); and 3) inadequate understanding of the non-linear dynamic (NLD) basis of cellular function and disease. We argue that the limit of understanding of cellular function/dysfunction and pharmacology based on empirical principles (observation/inference) has been reached, and that further progress depends on understanding these phenomena at the first principles theoretical level. Toward that end, we are developing and applying a theory on the mechanisms by which 1) cellular functions are conveyed by dynamic multi-molecular/-ionic (multi-flux) systems operating in the NLD regime; 2) cellular dysfunction results from molecular dysfunction; 3) molecular structure and function are powered by covalent/non-covalent forms of free energy; and 4) cellular dysfunction is corrected pharmacologically. Our theory represents a radical departure from the status quo empirical science and reduction to practice thereof, replacing 1) the interatomic contact model of structure-free energy and structure-property relationships with a solvation free energy model; 2) equilibrium drug-target occupancy models with dynamic models accounting for time-dependent drug and target/off-target binding site buildup and decay; and 3) linear models of molecular structure-function and multi-molecular/-ionic systems conveying cellular function and dysfunction with NLD models that more realistically capture the emergent behaviors of such systems. Here, we apply our theory to COVID Mpro inhibition and overview its implications for a holistic, in vivo relevant approach to drug design.